The present invention is related to sustained release formulations for the administration of locally active agents and/or diagnostic agents in sustained release form intra articularly or in other body spaces. In particular embodiments, the invention provides methods and compositions for the administration of local anesthetics as well as compositions and methods for augmenting the duration and potency of local anesthesia, in patients in need thereof, and for obtaining additional beneficial effects, in intra articular locations and in all human or animal body spaces.
Symptomatic treatment of joint pain has hereto been based on the use of systemic treatment with steroidal and nonsteroidal antiinflammatory agents and analgesics as well as localized injection of steroidal antiinflammatories, e.g., intra articular injection, and local anesthetics, either intra articular or proximal to the innervation of the painful joint. Localized treatment is generally preferred over systemic treatment, particularly when treating severe, localized joint pain, in order to avoid the untoward systemic effects associated with the high levels of both steroidal and nonsteroidal antiinflammatory agents otherwise required. Local anesthetics alone have previously been injected into joint spaces to relieve pain, with mixed results.
While compounds utilized as general anesthetics reduce pain by producing a loss of consciousness, local anesthetics act by producing a loss of sensation in the localized area of administration in the body. The mechanism by which local anesthetics induce their effect, while not having been determined definitively, is generally thought to be based upon the ability to interfere with the initiation and transmission of the nerve impulse. The duration of action of a local anesthetic is proportional to the time during which it is in actual contact with the nervous tissues. Consequently, procedures or formulations that maintain localization of the drug at the nerve greatly prolong anesthesia.
Local anesthetics are potentially toxic, yet must remain at the site long enough to allow sufficient time for the localized pain to subside. Therefore, it is of great importance that factors such as the choice of drug, concentration of drug, and rate and site of administration of drug be taken into consideration when contemplating their use.
Different devices and formulations are known in the art for administration of local anesthetics. For example, local anesthetics can be delivered in solution or suspension by means of injection, infusion, infiltration, irrigation, topically and the like. Injection or infusion can be carried out acutely, or if prolonged local effects are desired, localized anesthetic agents can be administered continuously by means of a gravity drip or infusion pump. Thus, local anesthetics such as bupivacaine have been administered by continuous infusion, e.g., for prolonged epidural or intrathecal administration.
Sustained release carriers for local anesthetics have been described. For example, U.S. Pat. Nos. 4,725,442 and 4,622,219 (Haynes) are directed to methoxyflurane-containing microdroplets coated with a phospholipid prepared by sonication, which are suitable for intradermal or intravenous injection into a patient for inducing local anesthesia. Such microdroplets are said to cause long-term local anesthesia when injected intradermally, giving a duration of anesthesia considerably longer than the longest acting conventional local anesthetic (bupivacaine).
U.S. Pat. No. 5,188,837 (Domb) relates to a microsuspension system containing lipospheres having a layer of a phospholipid imbedded on their surface. The core of the liposphere is a solid substance to be delivered, or the substance to be delivered is dispersed in an inert vehicle. The substance to be delivered can be, e.g., nonsteroidal anti-inflammatory compounds, local anesthetics, water insoluble chemotherapeutic agents and steroids.
Other formulations directed to injectable microcapsules, etc. are known. For example, U.S. Pat. No. 5,061,492 describes prolonged release microcapsules of a water-soluble drug in a biodegradable polymer matrix which is composed of a copolymer of glycolic acid and a lactic acid. The microcapsules are prepared as an injectable preparation in a pharmaceutically acceptable vehicle. The particles of water soluble drug are retained in a drug-retaining substance dispersed in a matrix of the lactic/glycolic acid copolymer in a ratio of 100/1 to 50/50 and an average molecular weight of 5,000-200,000. The injectable preparation is made by preparing a water-in-oil emulsion of an aqueous layer of drug and drug retaining substance and an oil layer of the polymer, thickening and then water-drying.
U.S. Pat. No. 4,938,763 (Dunn, et al.) is related to a biodegradable polymer for use in providing syringe able, in-situ forming, solid biodegradable implants for animals. In one aspect of this reference, a thermosetting system is utilized which utilizes copolymers which may be derived from polylactides and/or polyglycolides, combinations and mixtures of these and other polymers.
U.S. Pat. No. 4,293,539 (Ludwig, et al.) is directed to controlled release formulations comprised of a microbial agent dispersed throughout a copolymer derived from lactic acid and glycolic acid. The copolymer is derived from 60-95% lactic acid and 40-5% glycolic acid by weight, and has a molecular weight of 6,000-35,000. An effective amount of the copolymeric formulation is administered by subcutaneous or intramuscular administration.
WO 94/05265 describes improved biodegradable sustained release systems consisting of a polymeric matrix incorporating a local anesthetic for the prolonged administration of the local anesthetic agent. The devices are selected on the basis of their degradation profiles: release of the topical anesthetic in a linear, controlled manner over the period of preferably two weeks and degradation in vivo with a half-life of less than six months, more preferably two weeks, to avoid localized inflammation. The disclosure states that an anti-inflammatory can be incorporated into the polymer with the local anesthetic to reduce encapsulation for optimal access of drug to its site of action. The anti-inflammatories that are said to be useful include steroids such as dexamethasone, cortisone, prednisone, and others routinely administered orally or by injection.
Several non-glucocorticoids have been reported to prolong the action of local anesthetics. Epinephrine in immediate release form is known by those of ordinary skill in the art to briefly prolong the action of immediate release local anesthetics by inducing vasoconstriction adjacent to the site of injection. However, the duration of prolongation provided by immediate release epinephrine is on the order of about an hour, at best, in a highly vascularized tissue. This strategy is also severely limited by the risk of gangrene due to prolonged impairment of blood flow to local tissues. Dextrans and alkalinizing agents have also been suggested as local anesthesia prolonging agents, but have heretofore been reported to be ineffective for this purpose (Bonica et al., 1990, xe2x80x9cRegional Analgesia With Local Anestheticsxe2x80x9d THE MANAGEMENT OF PAIN, Second Edition, Volume II, Published, Lea and Febiger, Chapter 94, pages 1890-1892).
Colchicine has been shown to suppress injury-induced ectopic nerve discharge in a model system of chronic pain utilizing injured nerve (Wall et al.), 1995, Textbook of Pain, Third Edition, Publ., Churchill Livingston, pages 94-98; Devol et al., 1991, A Group Report: Mechanisms of neuropathic pain following peripheral injury. In: Basbaume A I, et al (eds). TOWARDS A NEW PHARMACOTHERAPY OF PAIN, Dahlem Konferenzen, Wiley, Chichester pp. 417-440; Devor et al., 1985, Pain, 22:127-137 at 128; and Devor, 1983, Pain 16:73-86). It has been reported in one study that colchicine was given for the treatment of low-back pain, although oral colchicine has been shown to be ineffective for the same indication (Schnebel et al., 1988, Spine 13(3):354-7). However, it has not heretofore been known to use colchicine to prolong local anesthesia.
A relatively long-acting local anesthetic, bupivacaine hydrochloride, is commercially available as Marcaine(copyright) Hydrochloride in sterile isotonic solutions with and without epinephrine (as bitartrate) 1:200,000 for injection via local infiltration, peripheral nerve block, and caudal and lumbar epidural blocks. After injection of Marcaine for caudal, epidural or peripheral nerve block in man, peak levels of bupivacaine in the blood are reached in 30 to 45 minutes, followed by a decline to insignificant levels during the next three to six hours.
In addition, polymer microparticles have long been used for both medical and non-medical applications where sustained release of an agent of interest is desired. Nevertheless, prior to the present invention, it would have been expected that polymer microparticles in a joint space would scratch the extremely smooth and slippery opposed intra articular surfaces or otherwise irritate or inflame the joint. Thus, the need for an effective method and formulation for delivering pain relief and other pharmaceutical or diagnostic treatments to the intra articular space has remained unmet until the present invention. Further, the need for an effective method and formulation for delivering pain relief and other pharmaceutical or diagnostic treatments to all body spaces has remained unmet until the present invention.
It is an object of the present invention to provide a biodegradable sustained release dosage form for providing prolonged administration of an active agent for the treatment and/or diagnosis of joint pain and/or other intra articular conditions in humans and animals. More particularly, it is an object of the invention to provide a local anesthetic in a biocompatible, biodegradable sustained release form in combination with an amount of an augmenting agent effective to enhance and prolong local anesthesia in joints and body spaces/cavities.
It is a further object of the present invention to provide a method for prolonging the effect of a local anesthetic agent in joints and/or body spaces/cavities and to further provide a prolonged and beneficial antiinflammatory effect.
It is a further object of the present invention to provide a biocompatible, biodegradable controlled release dosage form for providing prolonged local anesthetic treatment of body spaces in humans and animals, with or without other active agents described herein.
In accordance with the above-mentioned objects and others, the invention is related to formulations and methods for the localized and prolonged intra articular administration of active agents by the intra articular administration of a sustained release formulation according to the invention.
The sustained release formulation preferably comprises any agent suitable for the treatment or diagnosis of an intra articular condition.
The method according to the invention includes, for example, administering into an articular joint, a formulation of a biocompatible sustained release material and one or more active agents suitable for the purpose. The active agents can include one or more enzymes, anti-infectives, antibodies, and the like, diagnostic agents, as well as local anesthetics, local anesthesia augmenting agents and combinations thereof.
The active agents are preferably a local anesthetic and a non-toxic augmenting agent effective to potentiate or prolong the action of the local anesthetic effect. The sustained release material is in the form, e.g., of a plurality of microparticles including local anesthetic and said microparticles are suspended in a pharmaceutically acceptable vehicle for injection.
The formulation can include a local anesthetic augmenting agent, at least a portion of which is optionally incorporated in the sustained release material. In addition, at least a portion of the augmenting agent may optionally be in immediate release form.
In one aspect, the sustained release material comprises a polymer such as polyanhydrides, copolymers of acid and glycolic acid, poly(lactic) acid, poly(glycolic) acid, polyesters, polyorthoesters, proteins, polysaccharides and/or combinations thereof. Preferably, the polymers are biodegradable so that manual removal is avoided. Alternatively, the polymers are biocompatible and not biodegradable, in those circumstances wherein it is desirable to physically remove and/or wash out a local anesthetic formulation inserted into a joint space.
The sustained release formulation can contain any quantity of local anesthetic compatible with the selected polymer formulation. Preferably, the local anesthetic is incorporated into the sustained release material at a percent loading of 0.1% to 90% by weight. Any local anesthetic known to the art may be employed. Preferred local anesthetics include bupivacaine, ropivacaine, dibucaine, etidocaine, tetracaine, lidocaine, xylocaine, mixtures thereof, and/or salts and derivatives thereof.
Augmenting agents useful in potentiating pain relief and/or extending the duration of activity include, for example glucocorticosteroids, alphaxalone, allotetrahydrocortisone, aminopyrine, benzamil, clonidine, minoxidil, dehydroepiandrosterone, dextran, diazepam, diazoxide, ouabain, digoxin, spantide, taxol, tetraethylammonium, valproic acid, vincristine, a catecholamine in sustained release form, 1-[6-[[17-beta-3-methoxyestra-1,3,5(10)-triene-17-yl]amino]hexl]-1-H-pyrrole-2,5-dione, and active derivatives, analogs and mixtures thereof.
Useful glucocorticoid agents include, for example, dexamethasone, cortisone, prednisone, hydrocortisone, beclomethasone dipropionate, betamethasone, flunisolide, methylprednisone, paramethasone, prednisolone, triamcinolone, alclometasone, amcinonide, clobetasol, fludrocortisone, diflorasone diacetate, fluocinolone acetonide, fluocinonide, fluorometholone, flurandrenolide, halcinonide, medrysone.
One skilled in the art will appreciate that an augmenting agent can be optionally included in the extended duration local anesthetic formulation in an amount compatible with, e.g., the extended release material and/or in an amount selected to enhance or prolong the duration of pain relief to the extent desired. For example, an augmenting agent, or combinations of augmenting agents, is incorporated into the formulation substrate at a percent loading ranging from about 0.001% to about 30% by weight, preferably from about 0.005% to about 15%, by weight.
The augmenting agent is preferably effective to prolong the duration of local anesthesia in a treated joint from about 15% to about 1400% of the duration of local anesthesia induced by sustained release local anesthetic without the augmenting agent.
Dextran augmenting agents may have any suitable molecular weight, but preferably have a molecular weight ranging from about 20 kDa to about 200 kDa and are optionally incorporated into said substrate at a percent loading ranging from about 0.01% to about 30% by weight.
In addition, an augmenting agent can include or comprise a vasoconstrictor agent in sustained release form. Preferred vasoconstrictor agents include, for example, clonidine, guanfacine, guanabenz, dopa, methyldopa, ephedrine, amphetamine, methamphetamine, methylphenidate, ethylnorepinephrine, ritalin, pemoline, epinephrine, norepinephrine, dopamine, metaraminol, phenylephrine, methoxamine, mephentermine, ephedrine, methysergide, ergotamine, ergotoxine, dihydroergotamine, sumatriptan and analogs, including active metabolites, derivatives and mixtures of any of the foregoing.
The invention also provides formulations effective to provide localized pain relief when administered into an intra articular space. The formulation includes, for example, a local anesthetic incorporated in a sustained release formulation, an effective amount of a biocompatible material, and an amount of an augmenting agent effective to prolong the duration of the local anesthesia.
Microparticles according to the invention that are suitable for deposit at a site in a patient in need of local anesthesia can optionally be prepared in lyophilized form, e.g., for rehydration prior to use.
The formulation, e.g., in the form of lyophilized particles is also desirably prepared in unit dosage form that is sterilized and provided in a container including an amount of such lyophilized particles sufficient to induce prolonged local anesthesia in at least one patient upon suspension in a solution acceptable for deposit into a patient.
Examples demonstrate prolongation of the duration of local anesthesia with the greater prolongation being provided by the combination of a local anesthetic with either a glucorticoid or a non-glucocorticoid augmenting agent.
Preferably, the formulation is in a form suitable for suspension in isotonic saline, physiological buffer or other solution acceptable for injection into a patient.
In certain preferred embodiments of the invention, the local anesthetic is prepared in matrices of biodegradable controlled release injectable microspheres. Optionally, the augmenting agent is incorporated into these matrices along with the local anesthetic.
In further embodiments, a suspension comprising a plurality of biocompatible, biodegradable controlled release microspheres comprising a local anesthetic agent, together with an augmenting agent is incorporated in the controlled release microspheres, or dissolved or suspended in the suspension of microspheres. The suspension is, for example, suitable for administering the microspheres by injection.
In yet additional embodiments of the present invention, the local anesthetic is incorporated into a controlled release matrix having the augmenting agent coated on the surface thereof.
In yet additional embodiments of the invention, the formulation comprises a local anesthetic core; an augmenting agent present in the core in an amount effective to prolong the effect of the local anesthetic in an environment of use, and a biocompatible, biodegradable coating on the core providing a slow release of the local anesthetic and/or augmenting agent in an environment of use.
In further embodiments, a portion or all of the local anesthetic is incorporated onto an outer surface of the coated substrate and a portion or all of the augmenting agent is optionally incorporated in the core, so that, e.g., augmenting agent continues to be released after the local anesthetic has dispersed from the controlled release material.
The augmenting agent may be systemically administered by injection or infiltration, instillation, oral dosing or other method to obtain the desired prolongation of effect. Systemic administration, (e.g., oral or intravenous) while effective, will require a higher total dose of an augmentation agent than with local administration in proximity to the local anesthetic.
The controlled release local anesthetic dosage form may be injected or infiltrated, with or without an augmenting agent, at the site where the anesthetic is to be released. This can be prior to surgery, at the time of surgery, or following removal (discontinuation) or reversal of a systemic anesthetic.
In one preferred embodiment, the formulation is prepared in the form of microspheres. The microspheres may be prepared as a homogenous matrix of a local anesthetic with a biodegradable controlled release material, with the augmenting agent optionally incorporated therein. The microspheres are preferably prepared in sizes suitable for infiltration and/or injection, and injected at the site where the anesthetic is to be released before surgery, during the time of surgery, or following removal or reversal of systemic anesthetic.
Examples of intra articular joints where the formulations useful in the invention can be administered include knee, elbow, hip, sternoclavicular, temporomandibular, carpal, tarsal, wrist, ankle, and any other joint subject to arthritic conditions; examples of bursae where the formulations useful in the invention can be administered include acromial, bicipitoradial, cubitoradial, deltoid, infrapatellar, ishchiadica, and other bursa known to those skilled in the art to be subject to pain.
The formulations of the invention are also suitable for administration in all body spaces/cavities, including but not limited to pleura, peritoneum, cranium, mediastinum, pericardium, bursae or bursal, epidural, intrathecal, intraocular, etc.
The invention is further directed to the use of a formulation comprising (a) controlled release microparticles comprising a local anesthetic and an effective amount of a biocompatible, biodegradable sustained release material prolonging the release of the local anesthetic from the formulation, and (b) a non-toxic augmenting agent in an amount effective to prolong the effect of the local anesthetic in-vivo, to treat localized joint pain or pain arising from a body space. Preferably, at least a portion of said augmenting agent is incorporated into said microparticles.
The microparticles are preferably suspended in a pharmaceutically acceptable vehicle for injection. The formulation may further comprise an active agent selected from the group consisting of an enzyme, an anti-infective agent, an antibody, a diagnostic aid, a radio-opaque dye, a magnetic resonance imaging dye, a radiolabeled agent, and combinations thereof. Preferably, at least a portion of said further active agent is incorporated into said microparticles. The local anesthetic is preferably incorporated into the microparticles at a percent loading of 0.1% to 90% by weight. In certain preferred embodiments, the local anesthetic is bupivacaine, the augmenting agent is dexamethasone, and the sustained release material is a poly(lactide co-glycolide). In further preferred embodiments, the microparticles comprise local anesthetic in a percent loading between 0.1% and 90%, preferably between 65 and 80%, and augmenting agent is a glucocorticosteroid agent present in a weight percent relative to the local anesthetic from 0.005% to 15%.
The invention further is directed to the use of a formulation comprising (a) controlled release microparticles comprising a local anesthetic and an effective amount of a biocompatible, biodegradable sustained release polymer selected from polyanhydrides, copolymers of lactic acid and glycolic acid, poly(lactic) acid, poly(glycolic) acid, polyesters, polyorthoesters, proteins, polysaccharides and combinations thereof, providing an in-vitro release of said local anesthetic of from 10 to 60 percent after 24 hours, from 20 to 80 percent release after 48 hours, and from 40 to 100 percent release after 72 hours; and (b) a non-toxic augmenting agent in an amount effective to prolong the effect of the local anesthetic in-vivo, for providing pain relief a body space selected from pleura, peritoneum, cranium, mediastinum, pericardium, bursae or bursal, epidural, intrathecal, and intraocular, or from intra articular joints selected from knee, elbow, hip, sternoclavicular, temporomandibular, carpal, tarsal, wrist, ankle, and any other joint subject to arthritic conditions, or from bursae selected from acromial, bicipitoradial, cubitoradial, deltoid, infrapatellar, ishchiadica, and other bursa known to those skilled in the art to be subject to pain, and which formulation when administered in-vivo for at least about 24 hours, and preferably for 3-5 days. The formulation may in certain embodiments preferably comprise a second active agent selected from an enzyme, an anti-infective agent, an antibody, a diagnostic aid, a radio-opaque dye, a magnetic resonance imaging dye, a radiolabeled agent, and combinations thereof.